Chronic HBV and HDV infections are worldwide problem, causing severe liver injury with a major risk of liver cancer. A number of host proteins have been identified as putative receptors for HBV and HDV binding to target cells, but these receptors fail to support subsequent viral entry and the initiation of viral genome replication when expressed in liver cell lines that are not susceptible to HBV or HDV infection. To elucidate the molecular details mediating viral attachment and entry, the following specific aims are proposed: (1) Various natural and mutated forms of HBV envelope proteins will be used to determine optimal conditions for the controlled assembly of HDV particles that contain the HDV RNA genome; (2) These particles will then be used to test hypotheses regarding the requirements of proteolytic cleavage for virus attachment, entry and the initiation of genome replication. The results from this proposed research could lead to the development of antiviral strategies and of therapeutic treatment for chronic hepatitis patients. [unreadable] [unreadable]